Apotex Inc v. Wyeth LLC

1. Case Identification

• Case #: IPR2014-00115
• Patent #: 7,879,828
• Filed: November 1, 2013
• Petitioner(s): Apotex Inc.
• Patent Owner(s): Wyeth LLC
• Challenged Claims: 1-23

2. Patent Overview

• Title: Pharmaceutical Compositions of Tigecycline
• Brief Description: The ’828 patent relates to stabilized pharmaceutical compositions containing the antibiotic tigecycline, the excipient lactose, and an acid (hydrochloric or gentisic acid) to adjust the pH of the composition in a solution. The invention addresses degradation of tigecycline, particularly through epimerization at acidic pH levels.

3. Grounds for Unpatentability

Ground 1: Claims 1-23 are obvious over CN '550.

• Prior Art Relied Upon: CN '550 (Chinese Patent Publication No. 1390550A).
• Core Argument for this Ground:
  • Prior Art Mapping: Petitioner argued that CN '550 disclosed every limitation of the independent claims except for the use of tigecycline. CN '550 taught lyophilized compositions of minocycline (a known structural analog of tigecycline) stabilized with saccharide excipients, including lactose, and adjusted with hydrochloric acid to a preferred acidic pH range of 2.0-3.5, which overlaps the claimed range of about 3.0 to 7.0.
  • Motivation to Combine: Not a combination ground, but Petitioner argued a person of ordinary skill in the art (POSITA) would be motivated to substitute tigecycline for minocycline in the CN '550 formulation. This motivation stemmed from tigecycline's known effectiveness against antibiotic-resistant bacteria, making it a desirable candidate for a stable, injectable formulation.
  • Expectation of Success: A POSITA would have a high expectation of success because tigecycline and minocycline are close structural analogs sharing identical A and B rings, where the key C4 epimerization reaction occurs. Therefore, a formulation known to stabilize minocycline against degradation (including epimerization) would be expected to work predictably for tigecycline.

Ground 2: Claims 1-23 are obvious over CN '550 in view of Pawelczyk and Naggar.

• Prior Art Relied Upon: CN '550, Pawelczyk (a 1982 journal article on minocycline degradation), and Naggar (a 1974 journal article on tetracycline stability).
• Core Argument for this Ground:
  • Prior Art Mapping: This ground built upon the base formulation disclosed in CN '550. Petitioner asserted that Pawelczyk and Naggar provided the rationale for optimizing the pH to the specific ranges recited in the dependent claims. Pawelczyk taught that oxidative degradation of minocycline is predominant above pH 5, while Naggar taught that epimerization of tetracyclines is most rapid between pH 3 and 4, with maximum stability in weakly acidic media of pH 4-5.
  • Motivation to Combine: A POSITA seeking to improve the stability of the tigecycline formulation based on CN '550 would consult prior art on tetracycline degradation pathways. Pawelczyk and Naggar directly addressed the two primary degradation pathways (oxidation and epimerization) and taught that a pH range of approximately 4-5 represents an optimal balance to minimize both. This would motivate a POSITA to adjust the pH of the CN '550 formulation to within the claimed ranges.
  • Expectation of Success: Given that Pawelczyk and Naggar provided specific, predictable data on how pH affects stability for the same class of compounds, a POSITA would reasonably expect to achieve enhanced stability for tigecycline by applying these teachings.

Ground 3: Claims 1-23 are obvious over CN '550 in view of Naggar and Zhang.

• Prior Art Relied Upon: CN '550, Naggar, and Zhang (Application # 2005/0020610).

• Core Argument for this Ground:

  • Prior Art Mapping: This ground provided a further rationale for selecting lactose specifically from the list of stabilizers in CN '550. Naggar taught inhibiting C4 epimerization by using a deprotonating agent. Zhang taught that lactose stabilizes another drug (tetrodotoxin) against epimerization by forming intermolecular hydrogen bonds that "lock" the relevant functional group, preventing the protonation that initiates degradation.
  • Motivation to Combine: A POSITA, guided by Naggar to seek a protonation inhibitor, would find in Zhang a specific mechanism explaining how lactose performs this function via hydrogen bonding. A POSITA would recognize this mechanism as directly applicable to stabilizing the C4 dimethylamino group of tigecycline, providing a strong motivation to select lactose over other excipients mentioned in CN '550 to solve the known epimerization problem.
  • Expectation of Success: The scientific principle of stabilization through hydrogen bonding described in Zhang is a well-understood chemical mechanism, leading to a high expectation that lactose would effectively stabilize tigecycline in the same manner.

• Additional Grounds: Petitioner asserted additional obviousness challenges based on combinations of CN '550 with Trivedi, Kirsch, Herman, and Lawter, relying on similar theories of optimizing stability and selecting known excipients.

4. Key Claim Construction Positions

• "about" (pH values): Petitioner argued that the term "about" preceding pH values should be construed to mean ±0.5. This was based on data in the ’828 patent specification showing that epimer content was "indistinguishable" across a range of pH 4.5 to 6.0, suggesting the endpoints are not critical.
• "about" (molar ratio): Petitioner argued the term "about" for molar ratios of tigecycline to lactose should be construed to mean ±20%. This was based on patent examples where compositions with varying molar ratios (from about 1:0.8 to 1:4.9) were described as having indistinguishable stability results.
• "in a solution": Petitioner proposed a broad construction encompassing any aqueous fluid containing the claimed components. This included the initial solution for lyophilization, the reconstituted solution, and the final diluted solution for intravenous administration, as all are described in the specification.

5. Key Technical Contentions (Beyond Claim Construction)

• Analog Predictability: A central technical argument was that the chemical mechanisms for C4 epimerization are identical for tetracycline, minocycline, and tigecycline because they share the same core A and B ring structures. This position supported the direct application of stability data and mechanisms from prior art on older tetracyclines to the claimed tigecycline compositions.
• Mechanism of Saccharide Stabilization: Petitioner contended that the stabilization of tetracyclines by saccharides like lactose was well understood to occur via intermolecular hydrogen bonding. It was argued that the hydroxyl groups on lactose form a hydrogen bond with the lone electron pair on the C4 dimethylamino nitrogen, inhibiting the protonation necessary for epimerization and providing a clear, predictable basis for its use.

6. Relief Requested

• Petitioner requested institution of an inter partes review and cancellation of claims 1-23 of the ’828 patent as unpatentable under 35 U.S.C. §103.